16-halo-1, 3, 5(10)-estratrien-17-ones and 17-ols



United States V 1 I'G-HALO-1,3,'5(10)=ESTRATRIEN-1l-0NES AND 17-0LS William F. Johns, Morton Grove, 11]., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Application June 20, 1958 Serial No. 743,508

6 Claims. (Cl. 260-3973) The present invention relates to l'6-halo-1,3,5(10)- estratriene derivatives which can be represented by the structural formula wherein X is a halogen and Z is selected from the group consisting of hydroxymethylene, (lower) alkanoyloxymethylene and carbonyl. Among the (lower)alkanoyl radicals which are suitable are particularly the acyl radicals of carboxylic acids such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, heptanoyl, and octanoyl.

The l6-chloro, l6-bromoand 16-iodo-l,3,5(l0)- estratrien-17-one derivatives of the present invention can be prepared by treating an appropriate 1,3,5 {10),16- estratetraen-17-ol (lower)alkanoate with the desired halogen in an inert solvent such as carbon tetrachloride, destroying the excess halogen and isolating the product. As a specific example, reaction of 1,3,5(10),l6-estratetraen-l7-ol acetate with chlorine in carbon tetrachloride solution followed by destruction of excess chlorine with sodium bisulfite and isolation of the product affords l6a-chloro-1,3,5(10)-estratrien-17-one.

Suitable 1,3,5 (10),l6-estratetraen-l7-ol alkanoates can be prepared by heating -1,3,5(10)-estratrien-17-one at about 150 for about 4 hours with the desired alkanoyl anhydride and p-toluenesulfonic acid and recovering the product. The l7-enol acetate is a particularly suitable intermediate and is prepared readily by the treatment of 1,3,5 (l)-estratrien-17-.one with isopropenyl acetate with a catalyst such as p-toluenesulfonic acid as described hereinafter.

The Mot-halogen.-1,3,5(l0)-estratrien-17-ones can be prepared also by treating 1,3, 5(10),l6-estratetraenl7-ol alkanoate with a halogenating agent such as N-halogensuccinimide, e.g. N-bromo, or N-iodosuccinimide, dcstroying the excess halogeuating agent and isolating the product. As a specific example, reaction of 1,3,5(10), l6-estratetraen-l7-ol acetate with N-iodosuccinimide in dioxane solution followed by destruction of excess iodine with sodium thiosulfate and isolation of the product affords 16a-iodo-1,3,5 (l0)-estratrien-l7-,one. The same compound is obtained by the use of iodine in carbon tetrachloride solution.

l 6a-iluoro l,3,5(l0)-estratrien-17-one can be made by treating the corresponding l6-iodo compound with silver fluoride in a-solvent such as acetonitrile. After the re action is' complete; the precipitated silver salts are removed, the solvent removed in vacuo and the product collected and purified.

The l6oz-halo-l,3,5(10)-estratrien-l7-ol derivatives of the present invention can be prepared by gtreating the desired l6-halo-l,3 ,5(l0)-estratrien-17-one with a reducing agent such as lithium aluminum hydride or'sodium borohydride and isolating the product. As a specific example, reaction of 16,a-chlorol, 3,5(10)-estratrienl7- one in tetrahydrofuran with lithium aluminum hydride followed by destruction or the excess lithium aluminum hydride with acid and isolation of the product aifords 16a-chloro-1,3,5(10)-estratrien-17-ol. Esterification of the 17-hydroxyl radical is accomplished by treatment with the desired (lower) alkanoic acid anhydride and pyridine at room temperature followed by isolation and recovery of the product.

The processes by which the compounds of the invention are made can lead to the formation of stereoisomeric products. In actualpractice it is found that one of the stereoisomers predominates and that .upon subjecting the crude reaction product to recrystallization, the crystalline product obtained consists substantially of a single stereoisomer which has been designated thefu isomer in the examples. A determination .of the s'tereochemical configuration of the predominant isomer-is not necessary in the identification of the compounds-or-in employing the claimed compositions in their intended applioations. The ,B-isomers can be prepared by treating 16oziodo-1,3,5(l0)-estratrien-17-one with a lithium halide. As a specific illustration, treatment of 1-60c-i0d0-'1,3,5(,l0)- estratrien-l7-one in dimethylformamide with lithium iodide at room temperature afiFords the ,1 6fl-iodo isomer.

The compounds of the present invention are useful because of their valuable pharmacological properties. Broadly, their usefulness can be said to result from the fact that they exhibit certain of the biological characteristics which are associated with the natural estrogenic hormones, while at the same time they exhibit remarkably little estrogenic activity -It is well known that certain applications of estrogenic hormones such as estrone and estradiol are limited and in many cases made entirely impractical because of the estrogenic effects they produce. One of these applications is in the treatment of degenerative diseases associated with abnormal cholesterol metabolism and deposition. It is recognized that estrogenic hormones exhibit an inhibitory and consequently beneficial efiect on the arterial deposition of cholesterol and it is widely agreed that this so-called antiatherogenic effect is achieved by a reduction in theserum ration of cholesterol .to phospholipids. This result is commonly, but not necessarily, accompanied both by a reduction in the serum concentration of cholesterol and an increase in the serum concentration of phospholipids. The reduction in the serum ratio of cholesterol can be designated as a lipid effect and regarded as a measure of anti-atherogenic activity; and for any particular compound quantitative comparisons can be made between this eiiect and the estrogenic effect associated therewith. It has been found that in the compositions of the present invention the ratio of the lipid effect to the estrogenic effect has been markedly increased over the corresponding ratios which are characteristic of the natural estrogenic hormones.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in. degrees centigrade C.). Quantities of materials areexpressed in parts byweight and in parts by volume which bear the same relation one to the other as kilograms to liters.

chloric acid are added cautiously.

EXAMPLE 1 16u-chloro-I,3,5(1i)) -estratrien-17-0ne A "solution of 10.8 parts byweight of l,3,5(l)-estra- "trien-17-o'ne in 400 parts by volume of isopropenyl ace- 'tate containing 4.0 parts by weight of p-toluenesulfonic acid is distilled slowly for 18 hours. cooled and diluted with benzene. sium carbonate is added and the mixture extracted with benzene. the benzene extracts washed with water, dried over magnesium sulfate and the solvent removed in vacuo.

The residue is dissolved in hexane and chromatographed 'quickly over fullers earth (sold under the trade name fFlorex). 2000 parts by volume of hexane, the solvent removed The chromatographic column is eluated with from the eluate in vacuo to yield 1.3.500),l -estratetraenby weight or 1,3.5(),16-

tetrachloride and 10 parts by weight of anhydrous potassium carbonate is stirred vigorously at 10-15 and to this solution is added during five minutes, 0.34 part by weight of chlorine dissolved in 30 parts by volume of carbon tetrachloride. Excess aqueous sodium thiosulfate is added and the solution is extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and'the solvent removed in vacuo.

The residue is crystallized from methanol to yield 160:-

"chloro-l,3,S(l0)-estratrien-l7-one, which melts at 163- 164", exhibits a specific rotation of +l66.5 in chloroform and exhibits an absorption maximum in the infra red spectrum at 5.72 microns.

By substituting an equivalent quantity of bromine for the chlorine used above and otherwise proceeding as described, l6u-bromo-l,3,S(l0)-estratien-l7-one is obtained which melts at 163166, exhibits a specific rotation of +l26 in chloroform and which exhibits an absorption maximum in the infrared at 5 .73 microns.

EXAMPLE 2 16a-i0d0-I,3,5(I0) -estratrien-17-0ne A solution of 1.4 parts by weight of l,3,5(10),l6- estratetraen-l7-ol acetate in 50 parts by volume of acetic acid containing 0.8 part by weight of mercuric acetate The solution is Excess aqueous potas- 17-01 acetate which, after recrystallization from hexane -meltsat 108111. i TA solution of 123' parts '-estrate'traen-17-ol acetate in 15 parts by volume of carbon at '15" is treated with a solution of 1.3 parts by weight A of iodine in 200 parts by volume of acetic acid with a stirring. The solution is stirred for an additional 10 min- -utes' and is then poured into excess aqueous potassium 16oc-ch loro-I ,3 ,5 10) -estratrien-1 7-0! To a slurry of 0.2 part by weight of lithium aluminum hydride in 25 parts by volume of ether is added with stirring while cooling to 0, a solution of 1.0 part by weight of 16a-chloro 1,3,5(10)-estratrien-17-one in 15 parts by volume of tetrahydrofuran. The solution is stirred for 10 minutes and then water and dilute hydro- The mixture is extracted with benzene, the'extra'ct washed successively with water and potassium bicarbonate solution and dried vacuo and the residue is dissolved in 20- parts byvolume of hexane and then chromatographed on parts by weight of fullers earth. The chromatographic column over-magnesium sulfate.v The solvent is removed in is washed with 500 parts by' volume 'of'he'x'ane and eluted with 2000 parts by volume of 5% benzene in hexane. The solvents are removed from the citrate and the resi due crystallized from hexane to yield 16rx-chloro-L3, 5(l0)-estratrien-l7a-ol.,which melts at 179180 and exhibits a specific rotation of +68 in chloroform.

The chromatographic column is washed with 1000 parts by volume of 10% benzene in hexane and eluted further with 2000 parts by volumeof 20% benzene in hexane. The solvent is removed from the eluate'in vacuo and the residue crystallized from hexane to yield 16achloro-1,3,5(10)-estratrien-l7fl-ol which melts at 114- 115 and exhibits a specific rotation of +79 in chloroform. r

By substituting an equivalent quantity of 16u-bromo- 1,3,5 (l0)-estratrien-17-one for the chloroanalog used above and otherwise proceeding as described above, the corresponding brom'o- -analogs ar'c'ob'tained l6m-bromol',3,5'( l0)-e'stratrien-l7d-ol which melts at 168169, and

exhibits a specific rotation of +74 in chloroform; and 16u-bromo-1,3,5(10)-estratrien-l7fl-ol which melts at l0O-l0l and exhibits a specific rotation of +77 in chloroform.

EXAMPLE 4 1 65-011 Zora-1 ,3,5 (1 0) -estralrien-1 7-one A solution of 4.8 parts by weight of l6a'-iodo-1,'3, 5(lO)-estratrien-17-one in partsby volume of. acetonitrile is heated at refiux for 16 hours in a Soxhletapparatus containing 25 parts by weight of silver-fluoride. The mixture is cooled to room temperature, the suspended silver salts removed by filtration and the filtrate diluted with 250 parts by volume of chloroform, the resulting solution washed thoroughly with water and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 25 parts by volume of benzene and 50 parts by volume of petroleum ether and chromatographed over a column of 30 parts by weight of magnesia silica gel adsorbent (known as Florisil). The chromatographic column is eluted with 1000 parts by volume of 75% benzene and petroleum ether, the solvents removed from the eluate in vacuo and the residue crystallized from benzenepetroleum ether to yield 16a-fiuoro-l,3,5(l0)-cstratrien- EXAMPLE 6 1 16e-chl0r0-1,3,5 (I 0) -estratrien 1 7,6-01' acetate A solution of 2 parts by. weight of l6-chloro-1,3, 5(10)-estratrien-17fi-ol in 40 parts by volume of pyridine and 20 parts by volume of acetic anhydride is heated at 100 for 30 minutes. The mixture is cooledand diluted with 400 parts by volume of water. The solid which precipitates is collected, washed with water, dried and recrystallized from aqueous acetone to yield chloro-l,3,5(10)-estratrien-17B-ol acetate which exhibits La specific rotation of +6inchloroform and an absorption maximum in the infrared spectrum at 5.73 microns.

5 6 What is claimed is: consisting of hydroxymethylene, lower alkanoyloxy- 1. A compound of the formula methylene and carbonyl.

\ 16-ch1oro-1,3,5(10)-estratrien-17-one.

. 16-bromo-1,3,5 10) -estratrien-17-one. 16-iodo-1,3,5(10)-estratrien-17-one.

. 16-chloro-1,3,5(10)-estratrien-17-ol.

. 16-bromo-1,3,5(10)-estratrien-17-ol.

wherein X is a halogen and Z is selected from the group 10 No references cited UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2328,84? March 15 1960 William F. Johns Column 3 line 14 for -"el,1iated" read eluted 18, for "108-111 read 109-111 read estratrien line line 36 for -"estratien" Signed and sealed this 6th day of September 1960.

(SEAL) Attest:

ERNEST W, SWIDER ROBERT C. WATSON Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA 